In recent years, many therapeutic antibody drugs have been developed and anti-CD40 antibody can be mentioned as one of the antibodies. CD40 is an antigen that is expressed on the surface of B cell, DC, macrophage, endothelial cell, epithelial cell or tumor cells thereof, and anti-CD40 antibodies acting on CD40 are largely classified into agonistic one (also called “agonistic antibody”) and antagonistic one (also called “antagonistic antibody”). B cell activation is known as an action of the agonistic antibody, and this antibody may be exemplified by an agonistic anti-CD40 antibody that is described in Patent Literature 1.
On the other hand, because CD40 plays an important role in immune responses, it is expected that immunosuppression for organ transplantation and therapeutic agents for autoimmune diseases can be developed by inhibiting the binding of CD40 and its ligand using the antagonistic antibody. In this case, antagonistic anti-CD40 antibody is required to inhibit the binding of CD40L to human CD40 and also, the antibody itself is required not to activate CD40.
Until now, many studies have been made on the anti-CD40 antibody, but most of the identified anti-CD40 antibodies are agonistic antibodies, and there are very few antagonistic antibodies identified, such as 4D11 (Patent Literature 1), 5D12 (Patent Literature 2) or the like. Among them, a modified 4D11 antibody (hereinafter, referred to as “4D11G4PE”) is disclosed in Patent Literature 3, and this modified antibody avoids expression of agonistic activity both in vitro and in vivo, compared to the original 4D11 antibody. For this reason, this modified antibody is expected to be very useful as the antagonistic anti-CD40 antibody in the immune suppression for organ transplantation or in the treatment of autoimmune diseases (Patent Literature 3).
By the way, the development of these therapeutic antibody drugs requires a specialized formulation technology, as well as a technology of modifying the antibody itself. In other words, proteins such as antibodies or the like have a high molecular weight, a plurality of different functional groups, and a complex three-dimensional structure, unlike the conventional chemical synthetic molecules. Therefore, when therapeutic antibodies are formulated, there is a demand for a technology of storing the antibodies while maintaining their three-dimensional structure and their biological activity or characteristics.
One of these antibody preparations is, for example, a lyophilized preparation as described in Patent Literature 4. However, the lyophilized preparation requires a complex preparation procedure for administration to impose a burden on the practitioner in the medical field, and concerns are also raised about the risk of bacterial contamination due to handling. On the contrary, a solution preparation requires a simple preparation procedure before administration, and thus the risk of bacterial contamination is reduced. In the medical field, therefore, the solution preparation is considered more preferable than the lyophilized preparation.
For medical use, antibody is generally administered via an intravenous or subcutaneous route. Of them, subcutaneous administration of injectable preparations or the like is sometimes performed because of administration convenience or the like. Since subcutaneous administration depends on the volume limit (typically 1.5 ml or less) and the required administration dose (typically 50 mg or more), it is often necessary to administer a high concentration antibody.
For example, when 2 mg/kg of antibody is administered to a patient every week and the average body weight of the patient is 70 kg, the administration dose of the antibody is 140 mg, and the antibody concentration for subcutaneous administration should be approximately 100 mg/ml (in this case, approximately 140 mg of antibody is contained in 1.4 ml).
However, the highly concentrated antibody preparation has several problems. One of the problems is occurrence of turbidity or insoluble foreign matter attributed to antibodies during treatment and/or preservation.
Non-Patent Literature 1 suggests that a high concentration protein preparation shows an increase in the viscosity and turbidity, and ionic strength affects the degree. Further, Non-Patent Literature 2 suggests a method for stabilizing high concentration antibodies by spray-drying.
However, Non-Patent Literature 1 does not propose a fundamental solution for suppressing viscosity and turbidity of the high concentration protein preparation. Further, in the spray-drying described in Non-Patent Literature 2, a complex preparation procedure for administration is also required to impose a burden on the practitioner in the medical field, and concerns are also raised about the risk of bacterial contamination due to handling, like in the lyophilized preparation.
The known solution preparation of anti-CD40 antibody is a solution preparation of 4D11 antibody that is described in Patent Literature 5, and stability of this preparation has been confirmed in a variety of tests. However, because this preparation has the antibody concentration of 10 mg/ml, it is hard to use this preparation as the solution preparation for subcutaneous administration.